Occlusive events of the cardiovascular system constitute a significant area of medical need for which current treatment modalities are inadequate. Examples of occlusive events include restenosis following stenting or angioplasty procedures, formation of occlusions either within or in the proximity of vascular grafts, atherosclerosis, negative remodeling following cardiovascular interventions and stenosis resulting from vascular injury. In each of these events, a reduction in the vessel lumen occurs, often as the result of plaque formation or cell proliferation, which causes a partial or complete occlusion of the vessel lumen. Therefore, the treatment objective in each case is to provide a means for inhibition, stabilization or reduction of such occlusive events within the cardiovascular system of the body.
A wide variety of treatment strategies have been investigated for the treatment of these conditions, including pharmacological drug therapy, bypass surgery, percutaneous angioplasty, mechanical stents, drug coated stents, lasers, atherectomy devices, ultrasound, cryotherapy and ionizing radiation. While each of these show some promise, significant limitations exist with each. The reasons for these limitations, while too numerous to mention here, are well known in the art.
Consequently, there exists a need for better methods of treatment of cardiovascular disease indications. In particular, a therapy is desired which provides a beneficial means for treating a localized region of a vessel or graft without causing systemic toxicities, damage to surrounding tissues or local injury of the vessel. Furthermore, it is desirable to provide a therapy whose primary mechanism of action does not rely on the induction of DNA damage.
One therapy that has recently been investigated for the treatment of these indications is Photodynamic Therapy (PDT). PDT is a relatively new modality that is under development for the treatment of such conditions as malignancies, locally diseased tissues, hyperproliferating tissues, pathogens and certain unwanted normal tissues. The PDT procedure is conducted by administering a photosensitizing drug to the desired treatment zone, by either local or systemic means, followed by exposure to photoactivating light. During a PDT procedure, a photoactivating light excites the photosensitizer drug that causes modification or destruction of tissue, which is the desired clinical effect.
In the case of systemic administration, photosensitizers accumulate to varying degrees within tissues depending on the pharmacokinetic and distribution profile of the photosensitizer and the target cell types comprising the tissues. Given this, key factors to be considered in selecting a photosensitizer drug for systemic administration are uptake and selectivity in the target tissue. In general, a significant amount of drug screening is conducted in order to identify a compound that has the appropriate uptake in the target tissue, while having limited uptake in the surrounding tissue that is not the target of the treatment. The chemical factors that enable certain photosensitizers to accumulate to a greater degree at a target site are not well understood. In addition, the biological factors that result in the preferential uptake of some photosensitizers in certain tissue types compared to others are not well understood. It is the prevailing view throughout the scientific community, however, that each photosensitizer has its own distribution and pharmacokinetic properties within different tissues and these properties can play a significant role in the relative usefulness of a drug for use in PDT. These properties of preferential uptake in target tissue have been utilized to date to provide the selectivity associated with PDT.
In the case of local drug administration, systemic uptake and distribution are considered to be less important. This view is based on the perception that the uptake kinetics are different in this case, being determined by the characteristics of the particular drug and the local drug delivery device. Furthermore, in the case of local drug administration, selectivity is generally viewed as being less important since the photosensitizer is delivered directly to the desired treatment site rather than to the surrounding tissues that are not the target of the treatment. In other words, the primary purpose of utilizing local drug delivery is to deliver a higher dose of drug to the target site than is delivered to the non-target tissues, thereby providing a selective treatment. An additional advantage of local administration is the possibility of using a lower total drug dose by selectively delivering the drug directly to the target tissue rather than systemically throughout the entire body.
Various photosensitizers have been investigated for treatment of cardiovascular disease indications. These include Photofrin (D. Eton, et al., Inhibition of Intimal Hyperplasia by Photodynamic Therapy Using Photofrin, J Surg Res, 53, 558-62, 1992), 5-Aminolaevulinic Acid (M. P. Jenkins, et al., Reduction in the Response to Coronary and Iliac Artery Injury with Photodynamic Therapy Using 5-Aminolaevulinic Acid, Cardiovascular Res, 1, 1-8, 1999), tin ethyl etiopurpurin, Visudynet® (G. M. Vincent, et al., Effects of Benzoporphyrin Derivative Monoacid on Balloon Injured Arteries in a Swine Model of Restenosis, SPIE vol 2671, 72-77, 1996), Antrin®, (S. G. Rockson, et al., Photoangioplasty: An Emerging Clinical Cardiovascular Role for Photodynamic Therapy, Circulation, 102, 591-96, 2000), phthalocyanines (P. Ortu, et al., Treatment of Arterial Intimal Hyperplasia with Photodynamic Therapy, Photodynamic Therapy and Biomedical Lasers, Elsevier Science Publishers, edited by P. Spinella, et al, 1992) and MV6401 (I. M. Leitch, et al., Photodynamic Therapy with the New Photosensitizer Drug MV6401 Prevents Neointima Formation in Balloon-Injured Rat Carotid Arteries, Circulation, (Suppl. II), Vol 102, No. 18, Abstr. 2059, p. II-423., 2000; C. A. Waters, et al., Photodynamic Therapy with the New Photosensitizer Drug, MV6401, Results in Targeted Cell Death of Neo-Intimal Lesions in Rat Arteries, Circulation, (Suppl. II), Vol. 102, No. 18, Abstr. 1208, p. II-247, 2000).
In the case of inhibition of neointima formation, a significant number of animal studies have been conducted to investigate the usefulness of PDT. These studies have used light at wavelengths of 630 nm and greater, employing both systemic and local drug delivery (P. Gonschior, et al., Endovascular Catheter-Delivered Photodynamic Therapy in an Experimental Response to an Injury Model, Basic Res Cardiol, 92, 310-19, 1997; D. Eton, et al., Inhibition of Intimal Hyperplasia by Photodynamic Therapy Using Photofrin, J Surg Res, 53, 558-62, 1992; S. G. Rockson, et al., Photoangioplasty: An Emerging Clinical Cardiovascular Role for Photodynamic Therapy, Circulation, 102, 591-96, 2000), and using both intravascular and external light delivery schemes.
Other studies have investigated the inhibition of neointima formation in natural vein grafts in which, prior to implantation, the graft receives a PDT treatment using 675 nm light (G. M. LaMuraglia, et al., Photodynarnic Therapy of Vein Grafts: Suppression of Intimal Hyperplasia of the Vein Graft but not the Anastomosis, J Vascular Surg, 21, 1995). Still further studies have investigated the reduction or stabilization of plaques in diseased artery animal models using a photosensitizer delivered systemically and excited with either external or intravascular light with a wavelength near 730 nm. These studies led to the application of PDT in human clinical trials using Lutetium texaphyrin (LuTex) in combination with a laser source having a wavelength near 730 nm (S. G. Rockson, et al., Photoangioplasty: An Emerging Clinical Cardiovascular Role for Photodynaniic Therapy, Circulation, 102, 591-96, 2000). These human clinical trials have two primary efficacy endpoints: inhibition of restenosis following angioplasty based interventions and reduction/stabilization of plaques in atherosclerotic lesions.
Although wavelengths of 630 nm and greater were utilized in the aforementioned studies, for each of the drugs listed above, the strongest absorption feature actually occurs at wavelengths less than 610 nm. Therefore, each of these drugs should be more efficient when using wavelengths less than 610 nm, as opposed to the red/infrared wavelengths that were actually used in these studies. Wavelengths of 630 nm and greater are referred to herein as red/infrared. Wavelengths less than approximately 630 nm roughly correspond to the other colors in the spectrum, e.g., orange, yellow, green, blue, etc. In fact, in every cardiovascular PDT investigation to date, excitation wavelengths of 630 nm or greater have been used, even though these do not provide the most efficient means of excitation.
The major advantage of using wavelengths greater than 630 nm is associated with the absorption of light by the hemoglobin in blood. Specifically, for wavelengths generally greater than 630 nm, absorption by hemoglobin is minimized, allowing these wavelengths to readily penetrate through blood. This reduces the need for exclusion of blood from the region between the light delivery device and the tissue to be treated, allowing the use of relatively simple light delivery devices. For example, S. G. Rockson, et al., Photoangioplasty: An Emerging Clinical Cardiovascular Role for Photodynamic Therapy, Circulation, 102, 591-96, 2000, has pointed out that the ideal photosensitizer for cardiovascular PDT should display maximal absorption in the range of 700-800 nm or 950-1100 nm. They have further stated the efficacy of their approach can be attributed to the selective uptake of their photosensitizer and the deep penetration of light through blood and tissue that is achievable at their longer 732 nm excitation wavelength.
On the other hand, the relatively deep light penetration in tissue for wavelengths of 630 nm and greater could lead to PDT-induced damage of surrounding tissues. Of course, this would only be the case if the photosensitizer does not have sufficient selectivity to the target tissue. However, given the use of local drug delivery and in the case of systemic administration, the perceived highly selective nature of photosensitizers, other studies have given little or no attention to the risk associated with PDT-induced damage of surrounding tissues.
A third factor that has led researchers to rely on wavelengths greater than 630 nm is based on the geometric falloff of light emitted from a cylindrical or point source. As light radiates outward from either a cylindrical source or a point source, it must decrease in intensity since it is gradually spread over an ever-increasing volume. This conclusion is a result of basic physics and is simply a consequence of the law of conservation of energy. Furthermore, even in the red/infrared portion of the spectrum, light undergoes relatively strong absorption and scattering by tissue. Therefore, in addition to the geometric falloff, both absorption and scattering limit the penetration depth of light into surrounding tissues, even in the red/infrared portion of the spectrum. The combination of this, along with the previously mentioned factors, has led to the exclusive use of wavelengths of 630 nm and greater in cardiovascular PDT studies to date.
While the perceived advantages of using red/infrared light in cardiovascular PDT treatment may appear sound, this view does not take into account the unexpected result that the sensitivity of surrounding tissues to the PDT effect is often greater than that of the target tissues. We have discovered that, even while accounting for the apparently high relative drug uptake in the target tissue achieved with either systemic or local drug administration and the rapid attenuation of red/infrared light generated from an intravascular cylindrical diffuser, unacceptably high PDT damage occurs beyond the target tissue before the therapeutic threshold is reached in the target tissue. The reasons behind this unexpected result cannot be definitively established due to the complexity of the model and the PDT interaction. However, it may be due to a combination of the penetration depth of red/infrared light and a relatively higher sensitivity of surrounding tissue to the PDT effect. This sensitivity may be due to a tendency of some photosensitizers to localize in more critical regions within cells of surrounding tissues or a tendency to cause shut down of critical vasculature or nerves in these tissues. Alternatively, the assumption of high localization, especially with systemic administration, is often based on the relative brightness observed using fluorescence microscopy. However, this may not necessarily be correct since phenomena such as fluorescent quenching can lead to erroneous conclusions with fluorescence microscopy. Furthermore, even more accurate measurement techniques, such as high pressure liquid chromatography (HPLC) or autoradiography do not provide significant information on cell binding sites or intracellular location.
We have discovered that photosensitizer selectivity alone is insufficient to ensure minimal damage to surrounding tissue while simultaneously providing the desired level of efficacy within the targeted cardiovascular tissue. A wide variety of tissue types, such as myocardium, lung, nerves, adjacent vessels, fat, etc. are typically located near target vessels. In practice, it is nearly impossible for a drug to have the necessary preferential uptake characteristics in the target tissue, while not being taken up to some degree in these surrounding tissues as well. We have found that in situations where such surrounding tissues contain some amount of the photosensitizer, there is an especially difficult challenge in the practical implementation of PDT using red/infrared light. Penetration of light in this wavelength range appears to cause undesired PDT treatment in important underlying tissues that are well beyond the desired treatment zone of the vessel, thereby making it difficult to control treatment depth. Furthermore, while in theory it might be possible to accurately control the treatment depth by delivery of a specific light dose at the surface of the vessel lumen, this may be difficult to achieve in practice, due to the variations in tissue optical properties as well as the difficulty in accurately controlling the light level at all surfaces when using intravascular light. Furthermore, drug uptake will vary within the target treatment zone (even for the same tissue type) and the optical properties of the target tissue will vary between patients. These various factors will lead to significant practical limitations associated with variations in treatment depth, especially for wavelengths of 630 nm and greater. In practice, some regions in the target treatment area will receive an insufficient depth of treatment while others well outside the target treatment area will incur detrimental PDT effects.
Accordingly, there is a continuing need for a cardiovascular PDT treatment that delivers light to sufficiently penetrate into the target tissue, while simultaneously preventing the light from significantly penetrating through the tissue surrounding the target area.